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The process of miRNAs in gene modulation. The miRNA primary transcript (pri-miRNA) forms a stem-loop structure or hairpin that is processed by the RNase III enzyme (Drosha) to create a precursor miRNA (pre-miRNA), and then processed by another RNase III enzyme (Dicer) to create mature miRNA. Mature miRNA is bound by an Argonaute proteins (AGO1-AGO4 in humans) and incorporates into an RNA-induced silencing complex (RISC). The roles of miRNAs in gene silencing might include inducing mRNA degradation or preventing mRNA from being translated. For color figures, please see online at: www.futuremedicine.com/doi/full/10.2217/BMM.15.89
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Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and geneti...
Citations
... The regulation of the transcriptome is modulated through a variety of pathways, including transcriptional initiation, RNA processing and post-translational modification, which can affect the expression of genes involved in the pathological or recovery processes of drug induced kidney disease (DIKD). miRNA plays an important role in regularizing drug metabolization and transportation, and is a potentially promising proxy marker to assess drug efficacy and safety [101]. Specifically, circulating miRNA levels regulate the gene activity when tissues are exposed to toxic substances, making them novel non-invasive and sensitive biomarkers for drug-induced tissue injury pathologies [102]. ...
Nephrotoxicity is a significant concern during the development of new drugs or when assessing the safety of chemicals in consumer products. Traditional methods for testing nephrotoxicity involve animal models or 2D in vitro cell cultures, the latter of which lack the complexity and functionality of the human kidney. 3D in vitro models are created by culturing human primary kidney cells derived from urine in a 3D microenvironment that mimics the fluid shear stresses of the kidney. Thus, 3D in vitro models provide more accurate and reliable predictions of human nephrotoxicity compared to existing 2D models. In this review, we focus on precision nephrotoxicity testing using 3D in vitro models with human autologous urine-derived kidney cells as a promising approach for evaluating drug safety.
... MicroRNAs are emerging as pharmacogenomic biomarkers capable of identifying drug treatment response [30]. By enhancing the reliability of asthma treatment regimens, a biomarker for ICS response might subsequently help reduce asthma morbidity. ...
Background:
Asthmatic patients' responses to inhaled corticosteroids (ICS) are variable and difficult to quantify. We have previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure of ICS response. MicroRNAs (miRNAs) have shown strong effects on asthma and inflammatory processes.
Objective:
The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma.
Methods:
Small RNA sequencing in peripheral blood serum from 580 children with asthma on ICS treatment from The Genetics of Asthma in Costa Rica Study (GACRS) was used to identify miRNAs associated with ICS response using generalized linear models. Replication was conducted in children on ICS from the Childhood Asthma Management Program (CAMP) cohort. The association between replicated miRNAs and the transcriptome of lymphoblastoid cell lines in response to a glucocorticoid was assessed.
Results:
The association study on the GACRS cohort identified 36 miRNAs associated with ICS response at 10% false discovery rate (FDR), three of which (miR-28-5p, miR-339-3p, and miR-432-5p) were in the same direction of effect and significant in the CAMP replication cohort. In addition, in vitro steroid response lymphoblastoid gene expression analysis revealed 22 dexamethasone responsive genes were significantly associated with three replicated miRNAs. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) revealed a significant association between miR-339-3p and two modules (black and magenta) of genes associated with immune response and inflammation pathways.
Conclusion:
This study highlighted significant association between circulating miRNAs miR-28-5p, miR-339-3p, and miR-432-5p and ICS response. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment.
... One single miRNA can regulate more than a hundred mRNA transcripts, and each mRNA transcript can be regulated by several miR-NAs. 1 Most of the transcriptome is predicted to be targeted by miRNAs so they are proposed to be involved in the regulation of all fundamental cellular processes and have already been shown to be involved in the regulation of apoptosis, proliferation, and differentiation. 2 Extracellular miRNAs are circulating in multiple body fluids, including blood in cell-derived membrane vesicles or as protein-miRNA complexes. The vesicle-bound miRNAs can furthermore be divided into exosomal and microvesicular miRNAs. ...
... Altogether, numerous studies reported that drug treatment was affecting circulating miRNA levels. 2 The identification of novel miRNA biomarkers and the development of miRNA profiling for drug discovery and safety testing could advance the use of miRNA biomarkers in noninvasive liquid biopsy for personalized medicine and drug safety assessment. 12 Chlorpromazine was a broadly used antipsychotic medication but reported cases of DILI have limited its use. ...
... Among numerous studies performed so far, some particular miRNAs can be perceived as suitable candidates, especially since most of them are commonly associated with different cancer types, including breast cancer. The idea of miRNA functioning as early biomarkers for the evaluation of drug efficacy and drug safety was proposed not only in cancer but also in other diseases, including multiple sclerosis [3], bipolar disorder [4], diabetes [5] and others [6]. Thus miRNA profiling, supported by bioinformatic analysis, is perceived as a specific and sensitive biomarker for evaluating drug efficacy/resistance and drug safety in patients [7]. ...
One of the most innovative medical trends is personalized therapy, based on simple and reproducible methods that detect unique features of cancer cells. One of the good prognostic and diagnostic markers may be the miRNA family. Our work aimed to evaluate changes in selected miRNA levels in various breast cancer cell lines (MCF7, MDA-MB-231, SK-BR-3) treated with doxorubicin or cisplatin. The selection was based on literature data regarding the most commonly altered miRNAs in breast cancer (21-3p, 21-5p, 106a-5p, 126-3p, 126-5p, 155-3p, 155-5p, 199b-3p, 199b-5p, 335-3p, 335-5p). qPCR assessment revealed significant differences in the basal levels of some miRNAs in respective cell lines, with the most striking difference in miR-106a-5p, miR-335-5p and miR-335-3p—all of them were lowest in MCF7, while miR-153p was not detected in SK-BR-3. Additionally, different alterations of selected miRNAs were observed depending on the cell line and the drug. However, regardless of these variables, 21-3p/-5p, 106a, 126-3p, 155-3p and 199b-3p miRNAs were shown to respond either to doxorubicin or to cisplatin treatment. These miRNAs seem to be good candidates for markers of breast cancer cell response to doxorubicin or cisplatin. Especially since some earlier reports suggested their role in affecting pathways and expression of genes associated with the DNA-damage response. However, it must be emphasized that the preliminary study shows effects that may be highly related to the applied drug itself and its concentration. Thus, further examination, including human samples, is required.
... miR-122, one of the most demonstrated miRNA biomarkers, is a crucial regulator of liver physiology and disease biology and has been reported as a predictive biomarker for drug-induced liver toxicity (DILI) (Howell et al. 2018;Llewellyn et al. 2021;Wang et al. 2009). Similarly, miRNAs monitorable in biofluids and specific to cardiotoxicity, kidney toxicity, neurotoxicity, pancreas toxicity, skeletal muscle toxicity, and dermal toxicity have been comprehensively reviewed (Koturbash et al. 2015;Marrone et al. 2015;Schofield et al. 2021). More specifically, miR-122, miR-133a, miR-124 and miR-217 have been established as novel biomarkers for early detection of drug induced injuries in liver, muscle, central nervous system, and pancreas, respectively (Schofield et al. 2021). ...
Drug-induced testicular injury (DITI) is one of the often-observed and challenging safety issues seen during drug development. Semen analysis and circulating hormones currently utilized have significant gaps in their ability to detect testicular damage accurately. In addition, no biomarkers enable a mechanistic understanding of the damage to the different regions of the testis, such as seminiferous tubules, Sertoli, and Leydig cells. MicroRNAs (miRNAs) are a class of non-coding RNAs that modulate gene expression post-transcriptionally and have been indicated to regulate a wide range of biological pathways. Circulating miRNAs can be measured in the body fluids due to tissue-specific cell injury/damage or toxicant exposure. Therefore, these circulating miRNAs have become attractive and promising non-invasive biomarkers for assessing drug-induced testicular injury, with several reports on their use as safety biomarkers for monitoring testicular damage in preclinical species. Leveraging emerging tools such as ‘organs-on-chips’ that can emulate the human organ’s physiological environment and function is starting to enable biomarker discovery, validation, and clinical translation for regulatory qualification and implementation in drug development.
... Understanding which cell types contribute to disturbances in EV profiles in complex biofluids is highly relevant to identify pharmacological targets but also to decide and follow up pharmacological interventions. Moreover, as proposed for miRNAs (Chorley et al., 2021;Koturbash et al., 2015), cell type EV signatures could be used in, for example, clinical trials to define which region of the kidney are drug effects most likely derived from and safety and efficacy. Some attempts have been made to shed light to this topic. ...
Extracellular vesicles (EV) are membranous particles secreted by all cells and found in body fluids. Established EV contents include a variety of RNA species, proteins, lipids and metabolites that are considered to reflect the physiological status of their parental cells. However, to date, little is known about cell-type enriched EV cargo in complex EV mixtures, especially in urine. To test whether EV secretion from distinct human kidney cells in culture differ and can recapitulate findings in normal urine, we comprehensively analysed EV components, (particularly miRNAs, long RNAs and protein) from conditionally immortalised human kidney cell lines (podocyte, glomerular endothelial, mesangial and proximal tubular cells) and compared to EV secreted in human urine. EV from cell culture media derived from immortalised kidney cells were isolated by hydrostatic filtration dialysis (HFD) and characterised by electron microscopy (EM), nanoparticle tracking analysis (NTA) and Western blotting (WB). RNA was isolated from EV and subjected to miRNA and RNA sequencing and proteins were profiled by tandem mass tag proteomics. Representative sets of EV miRNAs, RNAs and proteins were detected in each cell type and compared to human urinary EV isolates (uEV), EV cargo database, kidney biopsy bulk RNA sequencing and proteomics, and single-cell transcriptomics. This revealed that a high proportion of the in vitro EV signatures were also found in in vivo datasets. Thus, highlighting the robustness of our in vitro model and showing that this approach enables the dissection of cell type specific EV cargo in biofluids and the potential identification of cell-type specific EV biomarkers of kidney disease.
... Early releasing and miRNA tissue specification, when the injury is reversible, are the most valuable benefits in toxicology. Towards the assessment of drug safety, miRNAs were found to correlate with cardiotoxicity, hepatotoxicity and nephrotoxicity (68,69,70). This review article is focused on miRNA utilization in drug-induced cardiotoxicity. ...
The clinical efficacy of chemotherapy, as a recognized therapeutic approach for malignant diseases, usually has certain limitations due to its cardiotoxicity (CT) and consequent cardiomyopathy, or even heart failure. CT is defined as any cardiac injury connected with oncology treatment, whether it is chemo-, radio-, targeted or immunotherapy, or cancer by itself, and it represents a great challenge for clinicians in everyday practice. A wide spectrum of factors related to chemotherapy (type of drug, dose during each cycle, cumulative dose, schedule, method of application, combination with other cardiotoxic drugs or association with radiotherapy) and patient characteristics (age, presence of cardiovascular risk factors, previous cardiovascular disease) are the determining factors that influence the frequency of CT. Imaging methods for morphological and functional monitoring of the heart muscle are used for monitoring CT. The quest for diagnostic tools for early CT detection is of great significance. In line with this, the measurement of some cardiac biomarkers has found its place in clinical settings as an early determinant of myocardial injury. Therefore, in this review article, special attention will be paid to certain well-established, as well as certain novel cardiac biomarkers, and their role in recognizing asymptomatic CT, in order to gain deeper insight into their diagnostic utility.
... [31][32][33] Recently the role of miRNAs has been implicated in evaluating the efficacy of drugs, opening a new avenue of "miRNA pharmacogenomics" to study the effects of drug treatment on radiation-induced altered miRNA expression and biological pathways. [34][35][36][37] In the current study, in an effort to understand the radioprophylactic mechanism of CDX-301, we examined global changes in the expression of miRNAs and associated pathways in mice treated with or without CDX-301 24 h prior to TBI. Our analysis reveals radiationinduced alteration in the expression of miRNAs and processing enzymes (such as AGO2, DGCR8, and DICER1). ...
... 42 The alteration in serum miRNA expression has been revealed in mice exposed to TBI. 43 Time-dependent changes in miRNA expression have been demonstrated in serum, plasma, and whole blood of mice exposed to TBI. [44][45][46][47] Tissue-specific changes of miRNAs in murine liver, heart, and testis have been demonstrated in mice exposed to TBI. 48 In the analysis of the efficacy of drugs, the role of miRNAs has achieved substantial consideration and opened a new field known as miRNA pharmacogenomics, [34][35][36][37] which is the study of drug administration effect on the expression of miRNAs and their associated target genes and pathways. Small molecules or drugs could regulate miRNA biogenesis and expression at all three stages (before, during, and after) of transcription. ...
Risks of radiation exposure necessitate the development of radioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Herein we performed global microRNA profiling to further understand the mechanism of action of CDX-301. We find CDX-301 administration 24 h prior to total body irradiation (TBI) prevents radiation-induced dysregulation of microRNA biogenesis and expression in murine serum and spleen samples in a time- and tissue-dependent manner. Further analysis shows that activation of the HOTAIR regulatory pathway has a prominent function in radiation-induced injury responses, which is inhibited by pre-treatment with CDX-301. Moreover, CDX-301 attenuates radiation-induced dysregulation of several cellular functions such as inflammatory and immune responses. In corroboration, we also find that pre-treatment with CDX-301 restores the expression of bone marrow aplasia markers and inflammatory cytokines and growth factors, as well as the expression of genes associated with MAP kinase and TGFβ pathways that are altered by radiation. Our findings provide new insights into CDX-301-mediated molecular and cellular mechanisms and point to a possible novel radioprotective drug for the prevention of irradiation-induced injury and hematopoietic-acute radiation syndrome (H-ARS).
... Contrarily, both miR-21 and miR-22 were overexpressed in SEC/CDDP tumors compared to the non-resistant ones. miR-21 was found to be involved in CDDP resistance through targeting the tumor suppressor phosphatase and tensin homolog (PTEN) in gastric cancer (Hu et al. 2018) and neuroblastoma, and was overexpressed in CDDP-resistant cell lines (Koturbash et al. 2015). In another study, the sensitivity of MCF-7 cells to CDDP was enhanced by knockdown of dicer which is accompanied by lower expression of miR-21. ...
... While miRNAs are increasingly being explored as drug targets for cardiovascular conditions [50], accumulating evidences in pharmacogenomics have shown their potential involvement in drug response [51]. Patients in our study cohort were prescribed anticoagulants (~98%), anti-platelet drugs (~90%), statins (~96%), anti-hypertensive drugs (~69%), and anti-diabetic medication (~44%) for disease management. ...
Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with ischemic stroke compared with healthy controls. Samples were collected within 24 h of clinical diagnosis. Stringent analysis criteria of discovery (46 cases and 95 controls) and validation (47 cases and 96 controls) cohorts led to the identification of 10 differentially regulated miRNAs, including 5 novel miRNAs, with potential diagnostic significance. Hsa-miR-451a was the most significantly upregulated miRNA (FC; 4.8, FDR; 3.78 × 10-85), while downregulated miRNAs included hsa-miR-574-5p and hsa-miR-142-3p, among others. Importantly, we computed a multivariate classifier based on the identified miRNA panel to differentiate between ischemic stroke patients and healthy controls, which showed remarkably high sensitivity (0.94) and specificity (0.99). The area under the ROC curve was 0.97 and it is superior to other current available biomarkers. Moreover, in samples collected one month following stroke, we found sustained upregulation of hsa-miR-451a and downregulation of another 5 miRNAs. Lastly, we report 3 miRNAs that were significantly associated with poor clinical outcomes of stroke, as defined by the modified Rankin scores. The clinical translation of the identified miRNA panel may be explored further.
